Seven Swedish general practitioners, members of the Drug Therapy Committe within the Swedish Association of General Practice, have compiled the evidence available in the Cochrane Library on the effects of cobalamin (vitamin B12), folic acid (vitamin B9) and pyridoxine (vitamin B6) on dementia. Their conclusion is that there is no scientific evidence that the vitamins mentioned prevent, retard or improve cognitive dysfunction. The Rondel has previously touched these topics (1-3). The present paper provides food for thought. The original report was published in Swedish in the journal AllmänMedicin (Family Medicine) 2004; 2:17-19, which generously gave Bo Norberg a free permission to translate and abridge the work for The Rondel.

The sales of B vitamin combinations in Sweden rose tenfold from Jan 1, 2000, to Dec 31, 2003, from about one million defined daily doses (DDD) to ten million DDD per quarter.

Many elderly people are treated with cobalamin, sometimes combined with folic acid and pyridoxine. On the Swedish market, the sales of combined B vitamins have increased tenfold in the period 2000-2003 (Fig 1). It is reasonable to assume that the rise of sales is due to studies showing that low levels of cobalamin or folate or increased levels of homocysteine, a non-specific marker for B vitamin deficiency, are associated with cognitive dysfunction, dementia, and vascular diseases (1-3).

It has been clearly shown that cobalamin and folic acid lower elevated levels of homocysteine. However, this does not constitute evidence that intake of B vitamins also prevents, retards, or improves cognitive dysfunction, nor vascular disease. Such questions may be elucidated by controlled prospective randomised studies.

Within the frame of Cochrane Collaboration, three systematic reviews were made concerning the effect of cobalamin, folic acid, and pyridoxine on cognitive functions (4-6).

Only two studies were found, which met the quality criteria of a Cochrane analysis – prospective, randomised, double-blind intervention studies (4). In both studies, the patients were elderly persons with dementia and low levels of serum cobalamin. In one study (n=31, 6 dropouts), the treatment patients were given oral cobalamin, 10 or 50 microgram for one month. In the other study (n=11), the treatment patients were given parenteral cobalamin, 1 mg. No effect of cobalamin on cognitive function could be demonstrated by these studies One conclusion was that larger and better studies are needed in this field.

Among the studies, which did not meet quality criteria, two deserves commenting. In one study, 50 patients with low serum cobalamin levels were randomised to parenteral cobalamin treatment or no treatment (7). No effect of cobalamin treatment could be demonstrated. Another study was excluded, because it was not randomised (8). However, the deterioration rate was the same in the treatment group as in the compared group.

The second systematic review (5) focused on folic acid, with or without cobalamin, given to elderly healthy persons and elderly demented persons in order to prevent or retard impaired cognitive function. Four such studies of acceptable quality were found, one on healthy elderly women, three on elderly patients with mild to moderate impairment of cognitive functions, with or without diagnosis of folate deficiency. There was no demonstrable effect of folic acid, with or without cobalamin, on parameters of cognition and mood. In one study the combination of folic acid and cobalamin lowered the homocysteine levels, but had no positive effect on dementia

A Swedish study was not included due to methodological weaknesses (9). The study comprised 33 patients with dementia. They were categorized into four groups – mild-moderate dementia or severe dementia, with or without elevated levels of homocysteine. Those patients with mild-moderate dementia, combined with elevated homocysteine, were improved by treatment with oral cyanocobalamin, 1 mg daily, and oral folic acid, 5 mg daily, for two months. Other groups did not improve. The study lacked a placebo control group. and it has neither been confirmed nor corroborated by other studies. Thus, this study does not provide an evidence-based documentation for recommendation of treatment. Nevertheless, the study generated a hypothesis worth further testing.

The third systematic review (6) focused on pyridoxine and cognitive dysfunction. Two studies were found, which met the quality criteria. Both studies recruited healthy participants. None was able to demonstrate significant improvements of mood and cognitive functions.

In contemporary Sweden, there is a discrepancy between the use of B vitamins and the actual documentation of the effect of these vitamins (Fig 1). We recognize the appropriate use of these vitamins in deficiency states, such as anaemia or polyneuropathy. We are aware that confusion, much like confusion of dementia, may occur in rare cases of B vitamin deficiency (10). Nevertheless, B vitamin therapy for cognitive dysfunction lacks a basis of evidence at present (4-6). Therefore, well designed, randomised, controlled trials are needed.

At present, there is no scientific documentation that B vitamins prevent, retard, or improve impaired cognitive function. In our view too much B-vitamins now are prescribed without a firm basis of documented efficacy for the patient.

Peter Rosenberg
Södertulls Hälsocentral
Box 804
SE-801 30 Gävle, Sweden
e-mail: peter.rosenberg@lg.se

Anders Hernborg, Halmstad
Jan Håkansson, Krokom
Ingmarie Skoglund, Borås
Robert Svartholm, Boden
Ulla Söderström, Umeå
Rolf Wahlström, Eskilstuna

References

[1] Bolander-Gouaille C. Current state of homocysteine research [debate]. Rondel 2003; 16. URL: http://www.rondellen.net/debate16_eng.htm
[2] Jansson J-H. Homocysteine and dementia [evaluation]. Rondel 2002; 11. URL: http://www.rondellen.net/evaluation11_eng.htm
[3] Norberg B..Painful sensory neuropathy [editorial]. Rondel 2003; 16. URL: http://www.rondellen.net/publisher16_eng.htm
[4] Malouf R, Areosa Sastre A. Vitamin B12 for cognition (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Länk till abstract
[5] Malouf R, Grimley Evans J, Areosa Sastre A. Folic acid with or without vitamin B12 for cognition and dementia (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Länk till abstract
[6] Malouf R, Grimley Evans J. Vitamin B6 for cognition (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd. Länk till abstract
[7] Kwok T, Tang C, Woo J, Lai WK, Law LK, Pang CP. Randomized trial of the effect of supplementation on the cognitive function of older people with subnormal cobalamin levels. International Journal of Geriatric Psychiatry 1998;13(9):611-6.
[8] Teunisse S, Bollen AE, Van Gool WA, Walstra GJM. Dementia and subnormal levels of vitamin B12 effects of replacement therapy on dementia. Journal of Neurology 1996;243:522-9.
[9] Nilsson K, Gustafson L, Hultberg B. Improvement of cognitive functions after cobalamin/folate supplementation in elderly patients with dementia and elevated plasma homocysteine. Int J Geriatr Psychiatry 2001; 16:609-14.
[10] Lerner V, Kanevsky M. Acute dementia with delirium due to vitamin B12 deficiency: a case report. Int J Psychiatry Med. 2002;32(2):215-20

Published June 9, 2004